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The generation of mature, functional, thyroid follicular cells from pluripotent stem cells would potentially provide a therapeutic benefit for patients with hypothyroidism, but in vitro differentiation remains difficult. We earlier reported the in vivo generation of lung organs via blastocyst complementation in fibroblast growth factor 10 (Fgf10), compound, heterozygous mutant (Fgf10 Ex1mut/Ex3mut) mice. Fgf10 also plays an essential role in thyroid development and branching morphogenesis, but any role thereof in thyroid organogenesis remains unclear. Here, we report that the thyroids of Fgf10 Ex1mut/Ex3mut mice exhibit severe hypoplasia, and we generate thyroid tissues from mouse embryonic stem cells (ESCs) in Fgf10 Ex1mut/Ex3mut mice via blastocyst complementation. The tissues were morphologically normal and physiologically functional. The thyroid follicular cells of Fgf10 Ex1mut/Ex3mut chimeric mice were derived largely from GFP-positive mouse ESCs although the recipient cells were mixed. Thyroid generation in vivo via blastocyst complementation will aid functional thyroid regeneration.

DOI： 10.3389/fendo.2020.609697

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The number of older patients with esophageal cancer (EC) is increasing due to the population aging and increasing life expectancy. However, no optimal treatment strategy for older patients with EC has been established to date. The aim of the present study was to review and compare the treatment modalities and outcomes of 990 younger and older patients diagnosed with EC in our institution. The patients were divided into younger (≤74 years) and older (≥75 years) groups. The majority of the patients in both groups had early-stage EC and were treated by endoscopic submucosal dissection (ESD). The older patients with locally advanced (stage II and III) EC were more likely to undergo chemoradiotherapy rather than esophagectomy. Among the older patients, 22% selected best supportive care. The disease-specific survival rate of the older patients was significantly lower compared with that of the younger patients, which was likely due to the less intense treatment modalities applied. The prognosis following esophagectomy was significantly better compared with that of chemoradiotherapy in the younger, but not in the older patients. In conclusion, the poorer prognosis of older patients (aged ≥75 years) with stage I EC may improve with multidisciplinary treatment after ESD. Although CRT is currently considered the optimal treatment for older patients with stage II/III EC, more efficient treatment modalities are urgently required.

DOI： 10.3892/mco.2019.1909

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Two patients underwent hemodialysis. Case 1 with stage IV gastric cancer was treated with reduced doses of capecitabine (1,000 mg/m2/day, days 1 to 14) and oxaliplatin (65 mg/m2, day 1). Although grade 1 thrombocytopenia occurred in the first cycle, grade 3 thrombocytopenia developed in the second cycle because of increasing dosage. After the dosage was reduced, chemotherapy was continued safely. Case 2 with stage IA gastroesophageal cancer was treated with radiotherapy followed by chemotherapy. Treatment with the same dose of CapeOX therapy as in case 1 resulted in no severe toxicity. We conclude that a half-dose of the CapeOX regimen is safe for gastric cancer patients undergoing hemodialysis.

DOI： 10.2169/internalmedicine.2718-19

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BACKGROUND: The timing, location, and level of gene expression are crucial for normal organ development, because morphogenesis requires strict genetic control. MicroRNAs (miRNAs) are noncoding small single-stranded RNAs that play a critical role in regulating gene expression level. Although miRNAs are known to be involved in many biological events, the role of miRNAs in organogenesis is not fully understood. Mammalian eyelids fuse and separate during development and growth. In mice, failure of this process results in the eye-open at birth (EOB) phenotype. RESULTS: It has been shown that conditional deletion of mesenchymal Dicer (an essential protein for miRNA processing; Dicer fl/fl ;Wnt1Cre) leads to the EOB phenotype with full penetrance. Here, we identified that the up-regulation of Wnt signaling resulted in the EOB phenotype in Dicer mutants. Down-regulation of Fgf signaling observed in Dicer mutants was caused by an inverse relationship between Fgf and Wnt signaling. Shh and Bmp signaling were down-regulated as the secondary effects in Dicer fl/fl ;Wnt1Cre mice. Wnt, Shh, and Fgf signaling were also found to mediate the epithelial-mesenchymal interactions in eyelid development. CONCLUSIONS: miRNAs control eyelid development through Wnt. Developmental Dynamics 248:201-210, 2019. © 2019 Wiley Periodicals, Inc.

DOI： 10.1002/dvdy.10

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DOI： 10.3892/ol.2018.9535

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DOI： 10.1089/ten.TEC.2018.0115

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Routledge  

The prognostic nutrition index (PNI), calculated based on serum albumin and lymphocyte counts, predicts the prognosis of several cancers, including operated esophageal cancers. In this study, we determined whether PNI could predict the occurrence of severe adverse events by chemotherapy and chemoradiotherapy, and overall survival in esophageal cancer. We collected data from 191 patients with esophageal cancer treated with at least one course of cisplatin and 5-fluorouracil from 2005 to 2016. We compared the incidences of severe adverse events and overall survival between a high- and a low-PNI group. The optimal cut-off value of the Onodera PNI was 43.2. Patients with low PNIs suffered more frequent severe adverse events than did those with high PNIs, and the latter patients survived longer. The PNI was independently prognostic of overall survival and stage. The PNI predicted the development of severe adverse events caused by chemotherapy or chemoradiotherapy, and overall survival, in esophageal cancer patients.

DOI： 10.1080/01635581.2018.1445765

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Background/Aim: Inhibition of glutaminolysis has been reported as a promising therapeutic strategy to target several solid carcinomas. We aimed to investigate the effects of glutaminolysis on cell proliferation in lung squamous cell carcinoma cell lines and to explore the potential of targeting glutaminolysis as an anticancer strategy. Materials and Methods: Glutamine (Gln) dependence was assessed in six lung squamous cell carcinoma cell lines. Cell proliferation, mammalian target of rapamycin complex 1 (mTORC1) activity and the induction of autophagy were assessed after inhibition of glutaminolysis via Gln depletion or glutaminase (GLS) inhibition. Results: Five of six lung squamous cell carcinoma cell lines exhibited glutamine- dependence. The extent of dependence was correlated with the mRNA levels of GLS1/GLS2. Inhibition of glutaminolysis inhibited cell proliferation by down-regulating of mTORC1 signaling and inducing autophagy in Gln-dependent lung squamous cell carcinoma cell lines. Conclusion: Targeting glutaminolysis may represent a potential therapeutic strategy for the treatment of Gln-dependent lung squamous cell carcinomas.

DOI： 10.21873/anticanres.11191

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

The American Society of Clinical Oncology provides clinical practice guidelines for appropriate cytotoxic chemotherapy dosing for obese adult patients with cancer. The panel recommends that actual body weight should be used when selecting cytotoxic chemotherapy doses regardless of obesity status. However, there have been no reports regarding the appropriate cytotoxic chemotherapy dosing for obese Japanese patients with cancer.
We collected data from 216 gynecological cancer patients who were treated with at least one course of a paclitaxel and carboplatin (TC) regimen or a docetaxel and carboplatin (DC) regimen at Niigata University Medical and Dental Hospital from July 2006 to April 2014. Patients were divided into three groups according to body mass index (BMI): obese (BMI aeyen 25), normal (BMI 18.5-24.9), and underweight (BMI < 18.5), as defined by the Japan Society for the Study of Obesity. We analyzed hematological toxicities by full weight-based chemotherapy in each group.
The rates of grade 3/4 leukocytopenia, neutropenia, and thrombocytopenia were not significantly different among the three BMI groups on all patient analyses. For the TC regimen, the obese and normal groups had significantly lower leukocytopenia (grade 3/4) rates than did the underweight group. Also, significant positive correlations between BMI and the nadirs of leukocytes, neutrophils, platelets, and hemoglobin were observed. For the DC regimen, no significant difference was observed among the BMI groups and the rate of grade 3/4 hematological toxicities.
We did not observe stronger myelosuppression in obese cancer patients compared with non-obese cancer patients. Therefore, the cytotoxic chemotherapy dose should be calculated by the actual body weight and unnecessary dose reduction should be avoided.

DOI： 10.1007/s00280-016-3119-2

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Pancreatic neuroendocrine tumors (pNETs) are an uncommon malignancy arising from the neuroendocrine cells of pancreas. Most cases of pNETs present with metastatic disease, but there are few reports in the literature describing pNETs metastasis to the lung and mediastinal lymph nodes [1]. Moreover, although a multimodal treatment including surgical resection and chemotherapy is acceptable for management of pNETs, advanced pNETs still remain a difficult therapeutic challenge [2, 3]. Radiotherapy or combined chemoradiotherapy has not been standard in the treatment of pNETs. An 80-year-old female was admitted to our hospital with cough and anorexia. She had been diagnosed and resected pNETs 8 years ago. Mass shadow was pointed out with chest X-ray, and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed. Pathological examination revealed neuroendocrine tumors, so the lung mass was considered as metastasis of pNETs. Then, we discussed her treatment at Cancer Board, and radiotherapy was chosen. We hope this case suggests that radiotherapy will be one of the treatment options for metastatic pNETs.

DOI： 10.1007/s13691-015-0230-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ALPHAMED PRESS  

Alveolar epithelial cells (AECs) differentiated from induced pluripotent stem cells (iPSCs) represent new opportunities in lung tissue engineering and cell therapy. In this study, we modified a two-step protocol for embryonic stem cells that resulted in a yield of similar to 9% surfactant protein C (SPC)(+) alveolar epithelial type II (AEC II) cells from mouse iPSCs in a 12-day period. The differentiated iPSCs showed morphological characteristics similar to those of AEC II cells. When differentiated iPSCs were seeded and cultured in a decellularized mouse lung scaffold, the cells reformed an alveolar structure and expressed SPC or T1 alpha protein (markers of AEC II or AEC I cells, respectively). Finally, the differentiated iPSCs were instilled intratracheally into a bleomycin-induced mouse acute lung injury model. The transplanted cells integrated into the lung alveolar structure and expressed SPC and T1 alpha. Significantly reduced lung inflammation and decreased collagen deposition were observed following differentiated iPSC transplantation. In conclusion, we report a simple and rapid protocol for in vitro differentiation of mouse iPSCs into AECs. Differentiated iPSCs show potential for regenerating three-dimensional alveolar lung structure and can be used to abrogate lung injury.

DOI： 10.5966/sctm.2013-0142

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Background: Putative resident stem/progenitor cells have been identified in the bronchoalveolar duct junction (BADJ) of the murine lung. However, the contribution of stem cells expressing both Clara cell secretory protein (CCSP) and pro-surfactant protein C (SP-C) to the repair and maintenance of normal homeostasis is still unclear. In this study, we identified and then quantified CD45neg/CCSPpos/SP-Cpos cell numbers in normal and lung-injured mice. Methods: Normal lung tissues of fetal, newborn, and adult mice were used to evaluate lung progenitor cells during development and growth. Mice treated with naphthalene were used for the bronchiolar epithelium injury model, and mice treated with bleomycin were used for the alveolar epithelium injury model. These lung tissues were stained with CD45, CCSP, and SP-C antibodies by immunofluorescence. The number of lung progenitor cells was counted as CD45neg/CCSPpos/SP-Cpos cells by flow cytometry. Results: CCSPpos/SP-Cpos epithelial cells in the BADJ were identified from E18 to 7 months after birth. The percentage of CD45neg/CCSPpos/SP-Cpos cells was relatively stable to 7 months (between 0.3±0.04% and 1.28±0.11%). When lungs were treated with naphthalene, the proliferation of CCSPpos/SP-Cpos cells was observed as patches of double-positive cells and preceded the recovery of bronchioles. In contrast, when lungs were treated with bleomycin, the proliferation of CCSPpos/SP-Cpos cells was observed, but the type II alveolar epithelial cells never recovered to baseline. Conclusions: CCSPpos/SP-Cpos lung cells were stable until 7 months after birth. These cells in the BADJ primarily regenerate bronchiolar epithelial cells and not alveolar epithelial cells. © 2013 The Japanese Respiratory Society.

DOI： 10.1016/j.resinv.2013.04.006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

Background: The Keap1-Nrf2 pathway has been reported to be impaired in several cancers. However, the status of Keap1-Nrf2 system in human colorectal cancer (CRC) has not been elucidated.
Methods: We used colorectal cancer (CRC) cell lines and surgical specimens to investigate the methylation status of the KEAP1 promoter region as well as expression of Nrf2 and its downstream antioxidative stress genes, NQO-1 and AKR1C1.
Results: DNA sequencing analysis indicated that all mutations detected were synonymous, with no amino acid substitutions. We showed by bisulfite genomic sequencing and methylation-specific PCR that eight of 10 CRC cell lines had hypermethylated CpG islands in the KEAP1 promoter region. HT29 cells with a hypermethylated KEAP1 promoter resulted in decreased mRNA and protein expression but unmethylated Colo320DM cells showed higher expression levels. In addition, treatment with the DNA methyltransferase inhibitor 5-Aza-dC combined with the histone deacetylase inhibitor trichostatin A (TSA) increased KEAP1 mRNA expression. These result suggested that methylation of the KEAP1 promoter regulates its mRNA level. Time course analysis with the Nrf2-antioxidant response element (ARE) pathway activator t-BHQ treatment showed a rapid response within 24 h. HT29 cells had higher basal expression levels of NQO-1 and AKR1C1 mRNA than Colo320DM cells. Aberrant promoter methylation of KEAP1 was detected in 53% of tumor tissues and 25% of normal mucosae from 40 surgical CRC specimens, indicating that cancerous tissue showed increased methylation of the KEAP1 promoter region, conferring a protective effect against cytotoxic anticancer drugs.
Conclusion: Hypermethylation of the KEAP1 promoter region suppressed its mRNA expression and increased nuclear Nrf2 and downstream ARE gene expression in CRC cells and tissues.

DOI： 10.1186/1471-2407-12-66

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